The differentiation of specific subsets of T cells is promoted by expression of the transcription factor retinoid-related orphan receptor-γ isoform-t (RORγt) (encoded by Rorc). RORγt is a member of the ROR family of transcription factors that transactivate gene expression by recruiting nuclear repressors or activators containing an LXXLL motif via their activating function-2 (AF2) domain to canonical ROR DNA binding sites through their DNA binding domain (DBD). In T cells, RORγt binds and activates the promoter of the Il17 gene to express the pro-inflammatory cytokine IL-17, driving the differentiation of conventional CD4+ TH cells (TH17) and sustaining innate-like gamma-delta (γδ) T cells. Phenotypic profiling of γδT cells identified two broad subgroups based on the expression of CD27, a member of the tumor necrosis factor receptor superfamily (TNFRSF). Thus, the CD27+ subset produces IFNγ whereas the CD27 subset produces IL-17. During development γδT cells are largely dependent on IL-7 signaling, which regulates the survival of early thymic progenitors and induces V(D)J recombination in the TCR-γ locus. Moreover, IL-7 maintains the homeostasis of γδT cells and preferentially expands the CD27−IL-17+ subset. The capacity of γδT cells to produce IL-17 is acquired during thymic differentiation, independently of TCR signaling, a feature pointing to their bona fide innate nature. γδT cells have emerged as potent inflammatory effectors that can be activated through innate as well as antigen receptors, either of which initiate rapid responses to infection.
RORγt is also essential for the differentiation of group 3 ILCs, such as lymphoid tissue inducer (LTi) cells, which are required for the development of secondary lymphoid organs, and in the adult IL-22 secreting ILCs (CD134+IL-22+ ILC), which are important for protection against intestinal infections and induce signals for survival of activated lymphocytes. The conservation of the ILC lineage in mice and primates underscores the importance of these cells in the rapid innate defense mechanisms in lymphoid tissues.
The broad expression profile in hematopoietic cells of the inhibitory receptor, B and T lymphocyte attenuator (BTLA) suggested a potential role in regulation of innate-like T cells and ILCs. BTLA belongs to the immunoglobulin superfamily, contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) and associates with the Src-homology domain 2 (SH2)-containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Through ligation with the herpesvirus entry mediator (HVEM, TNFRSF14) BTLA maintains the homeostasis of dendritic cells and memory T cells, and plays an important role in limiting T cell activation. In contrast to other inhibitory receptors that are induced following activation, BTLA is constitutively expressed in most immune cells. However, the levels of BTLA vary substantially among different lymphoid and myeloid cell types suggesting regulation of BTLA expression may be an important factor in controlling homeostasis in lymphoid tissues.
Herein it is demonstrated that RORγt and IL-7 influence γδT cell homeostasis and function by regulating expression of BTLA. The activating function-2 domain of RORγt is required to repress BTLA transcriptional activity, while IL-7 increases surface levels of BTLA. BTLA limits γδT cell numbers and sustains the normal distribution of γδT subsets by restricting IL-7 responsiveness and expansion of the CD27−RORγt+ population. Importantly, BTLA regulates IL-17 and TNF production. Consequently, BTLA-deficient animals exhibit enhanced disease in a γδT cell dependent model of dermatitis. Therefore, by coordinating expression of BTLA, RORγt and IL-7 balance suppressive and activation stimuli to regulate γδT cell homeostasis and inflammatory responses.